# Targeting Tris(2,3-dibromopropyl) Isocyanurate-Induced Inflammation in Hippocampal Neurons In Vitro: Mechanistic Insights and Implications for Neurodegenerative Disease Prevention

## TL;DR

This study explores how TBC, an environmental contaminant, harms hippocampal neurons and contributes to neurodegenerative diseases through inflammation and oxidative stress.

## Contribution

The study reveals that TBC induces neurotoxicity via NF-κB signaling and oxidative stress pathways in hippocampal neurons.

## Key findings

- TBC at higher concentrations reduces metabolic activity and increases apoptosis markers in hippocampal cells.
- TBC modulates NF-κB signaling and induces calcium release, contributing to neuroinflammation.
- Antioxidants and Keap1-Nrf2 pathway inhibitors reduce TBC-induced oxidative stress and inflammation.

## Abstract

Tris(2,3-dibromopropyl) isocyanurate (TBC) represents an emerging environmental contaminant with potential neurotoxic effects, attributable to its tendency to bioaccumulate and its capacity to traverse the blood–brain barrier. This study investigates the impact of TBC on cellular metabolism, membrane integrity or apoptosis-related caspase activity in mouse hippocampal cells, examining its interaction with key signaling pathways. Our results indicated that while TBC did not exhibit significant cytotoxicity at lower concentrations, prolonged exposure to higher concentrations substantially decreased metabolic activity and increased apoptotic marker activities (caspase-1, -3 and -9). Co-treatment with CAY10464 (AhR antagonist), GW9662 (PPARγ antagonist) and honokiol (NF-κB inhibitor) revealed that TBC significantly modulated NF-κB signaling, with notable reductions in AhR and IκBα protein expressions and altered levels of mTOR, NF-κB and p-IκBα proteins. Furthermore, TBC induced calcium release, supporting its role in neuroinflammatory responses. Moreover, TBC inhibited antioxidant enzyme activity and increased proinflammatory cytokine expression, implicating oxidative stress and inflammation in its neurotoxic effects. Antioxidants and Keap1-Nrf2 pathway inhibitors partially attenuated these responses, highlighting the role of oxidative stress pathways. These results suggest that prolonged TBC exposure may impair neuronal metabolism and activate apoptotic pathways, with NF-κB playing a pivotal role in mediating its neurotoxic effects.

The online version contains supplementary material available at 10.1007/s12035-025-05301-w.